Taxanes are chemically complex antineoplastic agents that were originally derived from the needles of the European yew tree. Often extremely potent, taxanes are notoriously insoluble in water. Efforts to attenuate the toxicities associated with taxanes, as well as attempts to improve their solubility, have focused on preparing conjugates of a water-soluble polymer covalently attached to a taxane. See, for example, WO 2010/019233.
Hydroxy groups on a drug represent useful points of attachment for a water-soluble polymer, and taxanes generally have several. The taxane drug, docetaxel, for example has four hydroxy groups, but only one of which—the “non-ring hydroxy”—is the preferred location at which a water-soluble polymer is attached.

In one approach for preparing water-soluble conjugates of docetaxel, a water-soluble polymer reagent that forms covalent bonds with hydroxy groups is reacted under conjugation conditions with docetaxel. Although such an approach is useful, a mixture of water-soluble polymer-docetaxel conjugates results wherein one, two or more polymers may be attached at any combination of hydroxy groups, e.g., as illustrated in the structure below:
In order to avoid results such as those depicted above and to obtain the desired product, additional purification steps or the use of protecting groups may be required, thereby adding cost and complexity to the synthesis of these compounds.
In another approach, docetaxel may be functionalized at the desired non-ring hydroxy group to provide a substituted docetaxel bearing an alternative functional group (e.g., amine). Although the alternative functional group may allow for more specific conjugation (e.g., because the alternative functional group is not present anywhere else within the molecule), similar to the aforementioned drawback associated with the water-soluble polymer reagent attaching at a variety of hydroxy groups, functionalization of, for example, amines at hydroxy groups also results in a mixture of substituted hydroxyl groups. Particularly in the context of prodrug approaches, random modification of hydroxy groups will release a version of the drug that is likely to retain at least some of the modified forms of the hydroxy group (rather than the hydroxy group itself), wherein such modified forms of the drug may not have the desired activity.
The challenge associated with competition among the various hydroxy groups within docetaxel is shared among all taxanes for which conjugation to a water-soluble polymer is desired. Only in the case of those that have capped hydroxy groups at positions 7 and 10, e.g. cabazitaxel has methoxy groups, will competition be essentially nonexistent, as the tertiary hydroxy group at ring position 1 is much less reactive than any of the secondary hydroxy groups.
It would therefore be useful to have an approach and compounds that avoid this competition among the several hydroxy groups of taxanes.
The present invention seeks to address these and other needs in the art.